Intravenous immunoglobulin (IVIG) preparations are increasingly used for the treatment of a variety of immunological deficiencies and autoimmune disorders including dermatomyositis, idiopathic thrombocytopenic purpura, Kawasaki disease, and Guillain-Barré syndrome. A small number of thromboembolic adverse events have been associated with the use of WIG preparations (Brannagan et al. Complications of intravenous immune globulin treatment in neurologic disease. Neurology 1996; 47:674-677; Rosenbaum J T. Myocardial infarction as a complication of immunoglobulin therapy. Arthritis Rheum 1997; 40:1732-1733; and Dalakas M C. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223-226).
These events, which include deep venous thrombosis and myocardial infarction, have primarily been observed in patients receiving high-dose WIG, and they have been attributed to an increase in blood viscosity (Dalakas M C. 1994; and Reinhart W H, Berchtold P E. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992; 339:662-664).
Components of the contact system of blood coagulation have previously been identified in human immunoglobulin preparations (Alving et al. Contact-activated factors: contaminants of immunoglobulin preparations with coagulant and vasoactive properties. J Lab Clin Med 1980; 96:334-346). Commercial preparations of immune serum globulin were shown to contain widely varying levels of prekallikrein activator (PKA) and kallikrein activity. These activities were of interest because of their potential to produce bioactive peptides that can increase vascular permeability. The presence of vasoactive fragments of these proteins was thought to be related to occasional adverse reactions during administration of immunoglobulin preparations. These authors also found factor XI (FXI) in immunoglobulin preparations (Alving et al. 1980).
In Alving et al. (1980) twenty-five lots of commercial Imune Serum Globulins (ISG) were analyzed for PKA and kallikrein, components of the contact activation system, which could mediate such reactions through the generation of kinins in recipients. Kallikrein activity ranged from undetectable levels to >60% of the total potential kallikrein activity in normal plasma. PKA ranged from 5% to 3950% of the activity in a reference plasma protein fraction that had caused hypotension. All but five lots increased vascular permeability in the guinea pig. The five lots which caused no increase were also the lowest in PKA and kallikrein activity. When the immunoglobulin preparation was subjected to gel chromatography to separate the enzymatic contaminants from immunoglobulin G, only the fractions containing PKA and/or kallikrein increased vascular permeability. Several lots of IVIG shortened the nonactivated partial thromboplastin time of normal plasma from 236 seconds to 38 to 55 seconds. During gel chromatography, coagulant activity was eluted in a position corresponding to a molecular weight of 150,000; which was inhibited by antibody to human factor XI. These data indicate that factor Xla is responsible for the procoagulant activity observed and that PKA and/or kallikrein are potential mediators of vasoactive reactions to IVIG preparation.
Immunoglobins have also been found to contaminate factor XI preparations. Factor XI and immunoglobulins co-purify through successive ion-exchange columns and require the addition of a specific concanavalin A affinity chromatography column to remove traces of IgG contamination from factor XI (Bonno B N, Griffin J H. Human blood coagulation factor XI: purification, properties, and mechanism of activation by activated factor XII. J Biol Chem 1977; 252:6432-6437).
Wolberg et al. (Coagulation Factor XI Is a Contaminant in Intravenous Immunoglobulin Preparations. Am J Hem 2000; 65:30-34) demonstrated that a procoagulant, identified as activated factor XI, is present in IgG preparations. In this study, twenty-nine samples of intravenous immunoglobulin (IVIG) from eight different manufacturers were assayed for procoagulant activity. Twenty-six of these samples shortened the clotting time of factor XI-deficient plasma. Of these, fourteen samples had factor XI activities greater than 0.001 U/ml of normal pooled plasma. The remaining samples possessed less than 0.001 U/ml of normal plasma activity. The procoagulant activity in these samples could be inhibited by an anti-factor XI polyclonal antibody, suggesting that the procoagulant activity was factor XI. The procoagulant activity increased in two samples after storage at 4° C. for 4 weeks, likely as a result of factor XIa autoactivation. Additionally, activity in some IVIG samples was able to directly activate factor IX, indicating that activated factor XI was present in these samples.
During the last 3 centuries numerous methods for purification of intravenous immunoglobulin has been developed to meet the growing demand for IVIG. The vast majority of the manufacturing process includes various technologies for capturing the immunoglobulin on a dedicated resin usually an ion exchange resin (Jerry Siegel. The Product: All Intravenous Immunoglobulins Are Not Equivalent. The Journal of Human Pharmacology and Drug Therapy. Volume 25, Issue 11 Part 2, November 2005). Capturing of immunoglobulin on a resin is very expensive and time consuming since it requires a large amount of resin. In average, every liter of ion exchange resin captures about 30-50 g immunoglobulin. Therefore, when using a conventional large column with a capacity of about 100 L resin, 3-5 Kg immunoglobulin can be captured. Capturing the agents present in the immunoglobulin solution by a small column has an economical benefit.
U.S. Pat. No. 5,252,217 discloses a human Factor XI concentrate prepared by applying a cryoprecipitated plasma supernatant to a filtration-adsorption step and a single step of chromatography on cation exchange resin. The concentrate obtained is perfectly suitable for therapeutic use in replacement therapy in cases of Factor XI deficiency. The cation exchange resin is equilibrated with a buffer solution at a pH of 5.5 to 6.5, and preferably a pH of 6.
U.S. Pat. No. 4,272,521 discloses a method for the removal of both prekallikrein activator (PKA) and kallikrein-activatable precursor to PKA (Factor XII) from an immune serum globulin (ISG) solution using an ion exchange material at a pH of 27.2.
U.S. Pat. No. 5,164,487 discloses a method of manufacturing an intravenously tolerable immunoglobulin-G preparation that is free of aggregates, vasoactive substances and proteolytic enzymes. The starting material is treated with 0.4 to 1.5% by volume of octanoic acid and then chromatographed, especially on an ion or cation exchanger or hydrophobic matrix.
United States Patent Application 2010/0311952 discloses a method for purifying an immunoglobulin, wherein the method comprises applying an aqueous, buffered solution comprising an immunoglobulin in monomeric and in aggregated form to a cation exchange material under conditions whereby the immunoglobulin in monomeric form does not bind to the cation exchange material, and recovering the immunoglobulin in monomeric form from the solution after the contact with the cation exchange material.
PCT application WO2010/072381 discloses a method for purifying an immunoglobulin, wherein the method comprises applying an aqueous, buffered solution comprising an immunoglobulin in monomeric, in aggregated, and in fragmented form to an anion exchange chromatography material under conditions whereby the immunoglobulin in monomeric form does not bind to the anion exchange material, and recovering the immunoglobulin in monomeric form in the flow-through from the anion exchange chromatography material, whereby the buffered aqueous solution has a pH value of from 8.0 to 8.5. In one embodiment the anion exchange chromatography material is a membrane anion exchange chromatography material.
Jose et al. (2010) discloses that pasteurization during Immune Globulin Intravenous production inactivates some thrombogenic agents such as clotting enzymes. However, this method does not selectively inactivate the clotting enzymes and thus may alter the activity of the immunoglobulin solution.
Thus, there is a need for a method which selectively removes thrombogenic agent from an immunoglobulin solution without affecting the immunoglobulins.